Publications by authors named "Alicja Urbaniak"

14 Publications

  • Page 1 of 1

Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models.

Biomed Pharmacother 2021 Jun 12;141:111815. Epub 2021 Jun 12.

Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.

Breast cancer remains one of the leading cancers among women. Cancer stem cells (CSCs) are tumor-initiating cells which drive progression, metastasis, and reoccurrence of the disease. CSCs are resistant to conventional chemo- and radio-therapies and their ability to survive such treatment enables tumor reestablishment. Metastasis is the main cause of mortality in women with breast cancer, thus advances in treatment will depend on therapeutic strategies targeting CSCs. Salinomycin (SAL) is a naturally occurring polyether ionophore antibiotic known for its anticancer activity towards several types of tumor cells. In the present work, a library of 17 C1-single and C1/C20-double modified SAL analogs was screened to identify compounds with improved activity against breast CSCs. Six single- and two double-modified analogs were more potent (IC range of 1.1 ± 0.1-1.4 ± 0.2 µM) toward the breast cancer cell line MDA-MB-231 compared to SAL (IC of 4.9 ± 1.6 µM). Double-modified compound 17 was found to be more efficacious than SAL against the majority of cancer cell lines in the NCI-60 Human Tumor Cell Line Panel. Compound 17 was more potent than SAL in inhibiting cell migration and cell renewal properties of MDA-MB-231 cells, as well as inducing selective loss of the CD44/CD24 stem-cell-like subpopulation in both monolayer (2D) and organoid (3D) culture. The present findings highlight the therapeutic potential of SAL analogs towards breast CSCs and identify select compounds that merit further study and clinical development.
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http://dx.doi.org/10.1016/j.biopha.2021.111815DOI Listing
June 2021

Synthesis, anticancer activity and molecular docking studies of N-deacetylthiocolchicine and 4-iodo-N-deacetylthiocolchicine derivatives.

Bioorg Med Chem 2021 02 11;32:116014. Epub 2021 Jan 11.

Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland. Electronic address:

Colchicine is a plant alkaloid with a broad spectrum of biological and pharmacological properties. It has found application as an anti-inflammatory agent and also shows anticancer effects through its ability to destabilize microtubules by preventing tubulin dimers from polymerizing leading to mitotic death. However, adverse side effects have so far restricted its use in cancer therapy. This has led to renewed efforts to identify less toxic derivatives. In this article, we describe the synthesis of a set of novel double- and triple-modified colchicine derivatives. These derivatives were tested against primary acute lymphoblastic leukemia (ALL-5) cells and several established cancer cell lines including A549, MCF-7, LoVo and LoVo/DX. The novel derivatives were active in the low nanomolar range, with 7-deacetyl-10-thiocolchicine analogues more potent towards ALL-5 cells while 4-iodo-7-deacetyl-10-thiocolchicine analogues slightly more effective towards the LoVo cell line. Moreover, most of the synthesized compounds showed a favorable selectivity index (SI), particularly for ALL-5 and LoVo cell lines. Cell cycle analysis of the most potent molecules on ALL-5 and MCF-7 cell lines revealed contrasting effects, where M-phase arrest was observed in MCF-7 cells but not in ALL-5 cells. Molecular docking studies of all derivatives to the colchicine-binding site were performed and it was found that five of the derivatives showed strong β-tubulin binding energies, lower than -8.70 kcal/mol, while the binding energy calculated for colchicine is -8.09 kcal/mol. The present results indicate that 7-deacetyl-10-thiocolchicine and 4-iodo-7-deacetyl-10-thiocolchicine analogues constitute promising lead compounds as chemotherapy agents against several types of cancer.
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http://dx.doi.org/10.1016/j.bmc.2021.116014DOI Listing
February 2021

Limitations of an ex vivo breast cancer model for studying the mechanism of action of the anticancer drug paclitaxel.

Eur J Pharmacol 2021 Jan 30;891:173780. Epub 2020 Nov 30.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address:

Paclitaxel is widely used in the treatment of breast, ovarian, lung, and other cancers. Its primary mechanism is to prevent microtubule depolymerization causing loss of dynamic instability crucial for normal microtubule function leading to mitotic arrest. Prolonged mitotic arrest results in cell death as a secondary response. The effects of paclitaxel are typically studied in cell lines which precludes assessment of the possible influence of tumor-associated cells. We therefore examined paclitaxel action ex vivo in fresh explant cultures of human breast tumors. Surprisingly, we found that paclitaxel failed to induce tumor cell death in explant culture, in contrast to several other cytotoxic agents including salinomycin and vincristine. The lack of effect was not due to defective drug uptake, and furthermore, analysis of H&E stained tumor slices indicated that paclitaxel treatment caused defective (granular) mitosis and chromosomal condensation in 5-10% of tumor cells after 72 h. These results suggest that while paclitaxel was able to penetrate into the tumor slice and disrupt mitosis in cycling tumor cells, any ensuing cell death likely occurred beyond the useful lifetime of the tumor slices. We conclude that explant culture systems may be inappropriate for the study of cytotoxic drugs where a delay exists between the drug's primary and secondary modes of action.
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http://dx.doi.org/10.1016/j.ejphar.2020.173780DOI Listing
January 2021

Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells-in vitro and ex vivo study.

J Biochem Mol Toxicol 2020 Jun 5;34(6):e22487. Epub 2020 Mar 5.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N-carbamates of N-deacetyl-4-(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti-proliferative activity than COL (IC  = 8.6 nM) towards primary ALL cells in cell viability assays (IC range of 1.1-6.4 nM), and several were more potent towards primary IDCG3 (IC range of 0.1 to 10.3 nM) or MC (IC range of 2.3-9.1 nM) compared to COL (IC of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non-small-cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer.
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http://dx.doi.org/10.1002/jbt.22487DOI Listing
June 2020

Synthesis, biological evaluation and molecular docking studies of new amides of 4-chlorothiocolchicine as anticancer agents.

Bioorg Chem 2020 04 13;97:103664. Epub 2020 Feb 13.

Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland. Electronic address:

Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different β tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.
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http://dx.doi.org/10.1016/j.bioorg.2020.103664DOI Listing
April 2020

Synthesis and Anticancer Activity of Tertiary Amides of Salinomycin and Their C20-oxo Analogues.

ChemMedChem 2020 01 27;15(2):236-246. Epub 2019 Nov 27.

Department of Bioorganic Chemistry Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland.

The polyether ionophore salinomycin (SAL) has captured much interest because of its potent activity against cancer cells and cancer stem cells. Our previous studies have indicated that C1/C20 double-modification of SAL is a useful strategy to generate diverse agents with promising biological activity profiles. Thus, herein we describe the synthesis of a new class of SAL analogues that combine key modifications at the C1 and C20 positions. The activity of the obtained SAL derivatives was evaluated using primary acute lymphoblastic leukemia, human breast adenocarcinoma and normal mammary epithelial cells. One single- [N,N-dipropyl amide of salinomycin (5 a)] and two novel double-modified analogues [N,N-dipropyl amide of C20-oxosalinomycin (5 b) and piperazine amide of C20-oxosalinomycin (13 b)] were found to be more potent toward the MDA-MB-231 cell line than SAL or its C20-oxo analogue 2. When select analogues were tested against the NCI-60 human tumor cell line panel, 4 a [N,N-diethyl amide of salinomycin] showed particular activity toward the ovarian cancer cell line SK-OV-3. Additionally, both SAL and 2 were found to be potent ex vivo against human ER/PR , Her2 invasive mammary carcinoma, with 2 showing minimal toxicity toward normal epithelial cells. The present findings highlight the therapeutic potential of SAL derivatives for select targeting of different cancer types.
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http://dx.doi.org/10.1002/cmdc.201900593DOI Listing
January 2020

Synthesis, biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine as anticancer agents.

Bioorg Med Chem 2019 12 8;27(23):115144. Epub 2019 Oct 8.

Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland. Electronic address:

Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5-9 against primary ALL-5 (IC = 5.3-14 nM), 5, 7-9 against A549 (IC = 10 nM), 5, 7-9 against MCF-7 (IC = 11 nM), 5-9 against LoVo (IC = 7-12 nM), and 5, 7-9 against LoVo/DX (IC = 48-87 nM). These IC values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, β-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used.
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http://dx.doi.org/10.1016/j.bmc.2019.115144DOI Listing
December 2019

The response of phyllodes tumor of the breast to anticancer therapy: An and study.

Oncol Lett 2019 Nov 6;18(5):5097-5106. Epub 2019 Sep 6.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

Phyllodes tumors of the breast (PTB) are uncommon stromal-epithelial neoplasms, with the main recommended treatment being surgical removal. However, even with adequate resection, the risk of recurrence in the malignant form remains as high as 40%, and there is no recognized consensus on the most effective drugs for PTB. In the present study, an model of malignant phyllodes and derived primary cell cultures were used to evaluate the effectiveness of a panel of different drugs, including the Bcl-2/Bcl-xL inhibitor ABT-263, salinomycin (SAL), doxorubicin (DOX), paclitaxel (TAX), vincristine (VCR), colchicine (COL) and cisplatin (CIS). ABT-263, SAL and DOX were highly effective towards phyllodes spindle cells when assessed in the model, contributing to ~98% tumor cell death. Furthermore, ABT-263 was highly selective for tumor cells in this system, and exhibited little toxic effect on adjacent normal epithelial cells. Furthermore, consistent with findings in the model, ABT-263 was significantly less toxic towards MCF 10A non-tumorigenic breast epithelial cells compared with SAL and DOX. A conditional reprogramming strategy was subsequently used, involving Rho kinase inhibition, to successfully generate primary phyllodes tumor cells that could be cultured for several passages. The primary cells were sensitive to DOX with an IC of 0.40±0.07 µM in a standard viability assay and the preliminary results were obtained indicating sensitivity to ABT-263 and SAL. The present study demonstrated the feasibility of using explants and primary cells for drug discovery, selectively targeting PTB cells.
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http://dx.doi.org/10.3892/ol.2019.10823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781661PMC
November 2019

Effect of pomegranate fruit supplementation on performance and various markers in athletes and active subjects: a systematic review.

Int J Vitam Nutr Res 2019 Sep 12:1-15. Epub 2019 Sep 12.

Department of Morphological Sciences, Biology and Health Sciences, Faculty of Physical Culture in Gorzów Wlkp., University School of Physical Education in Poznań, Poland.

The aim of the study was to review recent findings on the use of POM supplements in athletes of various disciplines and physically active participants. Eleven articles published between 2010 and 2018 were included, where the total number of investigated subjects was 176. Male participants constituted the majority of the group (n = 155), as compared to females (n = 21). 45% of research described was conducted on athletes, whereas the remaining studies were based on highly active participants. Randomised, crossover, double-blind study designs constituted the majority of the experimental designs used. POM supplementation varied in terms of form (pills/juice), dosage (50 ml-500 ml) and time of intervention (7 days-2 months) between studies. Among the reviewed articles, POM supplementation had an effect on the improvement of the following: whole body strength; feeling of vitality; acute and delayed muscle fatigue and soreness; increase in vessel diameter; blood flow and serum level of TAC; reduction in the rate of increase for HR, SBP, CK and LDH; support in the recovery of post-training CK, LDH, CRP and ASAT to their baseline levels; reduction of MMP2, MMP9, hsCRP and MDA; and increased activity of antioxidant enzymes (glutathione peroxidase and superoxide dismutase). In the majority of reviewed articles POM supplementation had a positive effect on a variety of parameters studied and the authors recommended it as a supplement for athletes and physically active bodies.
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http://dx.doi.org/10.1024/0300-9831/a000601DOI Listing
September 2019

Contrasting effects of microtubule destabilizers versus stabilizers on induction of death in G1 phase of the cell cycle.

Biochem Pharmacol 2019 04 19;162:213-223. Epub 2018 Dec 19.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States. Electronic address:

Microtubule targeting agents (MTAs) have been reported to manifest their cytotoxic effects not only in mitosis but also in interphase. However, the relationship between phase-specific susceptibility and MTA concentration, especially with respect to microtubule integrity, remains poorly defined. In addition, whether microtubule stabilizers and destabilizers act similarly or differ in the ability to induce interphase death is unclear. In order to resolve these uncertainties, we report here the results of a systematic comparison of primary acute lymphoblastic leukemia (ALL) and HeLa cells treated with three different MTAs, namely the microtubule stabilizer paclitaxel and two microtubule destabilizers, vincristine, and eribulin. Both types of cells were sensitive to each MTA, with IC values in the sub-nanomolar to low nanomolar range. Primary ALL cells arrested in mitosis when treated with paclitaxel at all tested concentrations, whereas the effects of vincristine or eribulin were concentration-dependent; low (<30 nM) concentrations induced mitotic death whereas higher concentrations (>100 nM) induced death directly in G1 phase. G1 phase death in response to higher concentrations of the destabilizers was associated with complete loss of interphase microtubule structure. In contrast, HeLa cells were only susceptible in M phase regardless of drug type or concentration. These results represent an important advance in our understanding and appreciation of microtubule function, and indicate that susceptibility to MTAs in G1 phase is both cell type- and drug type-restricted. The findings have important implications for the clinical use of MTAs especially in the context of drug combinations.
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http://dx.doi.org/10.1016/j.bcp.2018.12.015DOI Listing
April 2019

Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes.

Bioorg Chem 2018 12 12;81:553-566. Epub 2018 Sep 12.

Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland. Electronic address:

A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4-14. These compounds have been obtained in a simple reaction of 7-deacetyl-10-thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4-8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC values = 0.009-0.014 μM). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization.
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http://dx.doi.org/10.1016/j.bioorg.2018.09.004DOI Listing
December 2018

Biological activity of doubly modified salinomycin analogs - Evaluation in vitro and ex vivo.

Eur J Med Chem 2018 Aug 10;156:510-523. Epub 2018 Jul 10.

Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 221 00, Lund, Sweden. Electronic address:

The polyether ionophore salinomycin has recently captured much interest due to its potent activity against multi-drug resistant cancer cells and cancer stem cells. Previous studies have shown that either acylation of the C20 position or esterification/amidation of the C1 carboxylate moiety is beneficial in terms of biological properties. In this paper, we present the first analogs combining such modifications. Evaluation of the anti-proliferative activity against a series of cancer cell lines showed that acylation of the C20 hydroxyl group improves the activity of salinomycin C1 amides but not of the corresponding C1 esters. Importantly, the activity of several of the doubly modified analogs surpasses that of commonly used cytostatic drugs cisplatin and doxorubicin in the LoVo/DX multi-drug resistant cell line. All analogs were tested against primary acute lymphoblastic leukemia cells in standard cell viability assays; three were more potent than salinomycin. Further studies revealed that selected analogs induced characteristics of apoptotic cell death and increased expression of p53. Additionally, using an ex vivo model of breast tumor, tumor cell viability significantly decreased after treatment with salinomycin or its double-modified derivative (3a) in a time-dependent manner. The present findings indicate that double-modified salinomycin derivatives constitute promising lead compounds for targeting various types of cancer.
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http://dx.doi.org/10.1016/j.ejmech.2018.07.021DOI Listing
August 2018

Salinomycin derivatives exhibit activity against primary acute lymphoblastic leukemia (ALL) cells in vitro.

Biomed Pharmacother 2018 Mar;99:384-390

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States. Electronic address:

Salinomycin (SAL) and monensin (MON) are polyether ionophore antibiotics commonly used in veterinary medicine. They are known from their anti-cancer activity against various types of cancer cells, including those that display multi-drug resistance as well as cancer stem cells. In order to increase the biological activity profile and reduce toxicity against normal cells, while retaining the activities in the micromolar range, a library of ester and amide derivatives of SAL was synthesized and previously reported. In this paper, we examined the activity of SAL, its ten derivatives, and MON on primary acute lymphoblastic leukemia cells. MON and six SAL derivatives were more potent than SAL in cell viability assays. Further, selected active SAL analogs induced characteristics of apoptotic cell death and increased expression of p53. Moreover, SAL acted synergistically with the Bcl-2 inhibitor ABT-263, whereas 2,2,2-trifluoroethyl ester, the most active analog of SAL, antagonized ABT-263, suggesting possible differences in molecular mechanism.
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http://dx.doi.org/10.1016/j.biopha.2018.01.081DOI Listing
March 2018

Activity of resveratrol triesters against primary acute lymphoblastic leukemia cells.

Bioorg Med Chem Lett 2017 06 9;27(12):2766-2770. Epub 2017 May 9.

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States. Electronic address:

Resveratrol is a common polyphenol of plant origin known for its cancer prevention and other properties. Its wider application is limited due to poor water solubility, low stability, and weak bioavailability. To overcome these limitations, a series of 13 novel resveratrol triesters were synthesized previously. In this paper, we describe the synthesis of 3 additional derivatives and the activity of all 16 against primary acute lymphoblastic leukemia cells. Of these, 3 compounds were more potent than resveratrol (IC=10.5µM) namely: resveratryl triacetate (IC=3.4µM), resveratryl triisobutyrate (IC=5.1µM), and resveratryl triisovalerate (IC=4.9µM); all other derivatives had IC values of >10µM. Further studies indicated that the active compounds caused G1 phase arrest, increased expression of p53, and induced characteristics of apoptotic cell death. Moreover, the compounds were only effective in cycling cells, with cells arrested in G1 phase being refractory.
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http://dx.doi.org/10.1016/j.bmcl.2017.04.066DOI Listing
June 2017
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